TitleDesign and synthesis of G-quadruplex selective macrocyclic polyoxazoles
NameRzuczek, Suzanne G. (author), Rice, Joseph E (chair), LaVoie, Edmond J (internal member), Williams, Lawrence J (internal member), Jones, Roger A (outside member), Rutgers University, Graduate School - New Brunswick,
Quadruplex nucleic acids,
DescriptionNucleic acid sequences that can form stable G-quadruplex structures have been implicated in numerous biological functions. G-quadruplexes are thought to play a vital role in telomere maintenance and regulating gene expression. The majority of cancer cells over-express telomerase, an enzyme that bypasses the aging process by adding telomeric repeats to chromosome ends. Also about 65% of oncogenes have a potential G-quadruplex forming sequence in their promoter region. It is believed that stabilized G-quadruplexes can indirectly inhibit telomerase and decrease oncogene expression resulting in cancer cell death. These observations have led to the development of small molecules that stabilize G-quadruplexes as a new class of anticancer agents. Several research groups have developed such molecules but most lack selectivity over other forms of DNA. A unique molecule among these is telomestatin, a macrocyclic natural product with 70-fold selectivity for G-quadruplex DNA over duplex and low micromolar cytotoxicity. Although telomestatin has exceptional activity, it is difficult to synthesize and hard to formulate because it lacks water-solubilizing groups. Initial studies utilized telomestatin as a lead structure to develop a novel class of macrocyclic hexaoxazoles with the most active compound being HXDV. It was shown to stabilize G-quadruplex DNA with no detectable interaction with duplex DNA and had comparable cytotoxic activity to telomestatin. Unfortunately, HXDV had limited aqueous solubility and required a lengthy synthesis. Efforts to modify the structure of HXDV to enhance water solubility and simplify the synthetic process are described in this dissertation. While this was generally successful, a shorter synthesis was needed to rapidly assess structure-activity relationships. This led to the development of a second class of compounds called macrocyclic pyridyl polyoxazoles (PyPX). These compounds utilize a molecular scaffold that is readily accessed in few synthetic steps to form numerous macrocyclic analogs. This enables quick assessment of structure-activity relationships. Several members of this class are excellent G-quadruplex stabilizers and do not interact with duplex DNA. These compounds also possess low nanomolar cytotoxicity and one was active in an in vivo bioassay. Structure-activity studies utilizing the PyPX scaffold continue in an effort to identify clinical candidates.
NoteIncludes bibliographical references
Noteby Suzanne G. Rzuczek
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.